Process for the preparation of tetranorlabdane derivatives

ABSTRACT

The present invention concerns a process for the preparation of a compound of formula (I) wherein the dotted line is a single bond and n is 1 or the dotted line is a double bond and n is 0, and wherein the relative configuration is as shown, in the form of any one of its diastereoisomers or enantiomers or mixtures thereof.

TECHNICAL FIELD

The present invention relates to the field of organic synthesis and morespecifically it concerns a process for the preparation of a compound offormula

wherein the dotted line is a single bond and n is 1 or the dotted lineis a double bond and n is 0, and wherein the relative configuration isas shown, in the form of any one of its diastereoisomers or enantiomersor mixtures thereof. The invention concerns also some of the startingcompounds.

PRIOR ART

The compounds of formula (I) are very well known perfuming ingredients,some of which of particular relevance. Therefore, there is always a needfor alternative synthesis to produce them.

Preparation of the compound (I) by cyclisation of compound (II) is avery attractive synthetic route, since atom economic andstraightforward. Such approach has been illustrated in the prior art by:

-   -   G. Frater and co-workers in WO 06/10287, wherein an unsaturated        alcohol similar to compound (II) is cyclised into the        corresponding tetrahydrofuran in the presence of a protic        mineral or organic acid (in the examples is used an excess of        methanesulphonic acid in CH₂Cl₂ at room temperature, yield about        60%);    -   A. De Groot et al, in Tetrahedron, 1994, 50, 10095, wherein an        unsaturated alcohol similar to compound (II) is cyclised into        the corresponding tetrahydrofuran in the presence of        para-toluenesulphonic acid in nitromethane at room temperature,        yielding compound (I) in about 70% and with diastereomers; or by    -   G. Ohloff et al, in Helv. Chem. Acta, 1985, 68, 2022, wherein an        unsaturated alcohol similar to compound (II) is cyclised into        the corresponding tetrahydrofuran in the presence of        para-toluenesulphonic acid in nitromethane at 100° C., yielding        compound (I), no yield indicated and not ratio between the        various isomers.

However, the conditions reported in the prior art suffer from variousproblems that limit their use in industrial processes. Indeed they arenot very environment friendly (excess of acids), provide the product inmoderate yield, and/or require use of hazardous solvents such asnitromethane.

Therefore, there is still a need for alternative methods to perform suchcyclisation and allow the use of more environmentally friendlyconditions, and/or higher yields for instance and/or lower amounts ofundesired isomers.

To the best of our knowledge, it is the first time that is reported aneffective, cyclisation of an alcohol (II) into a compound (I).

DESCRIPTION OF THE INVENTION

We have now found that a compound of formula (I) as defined below, e.g.(3aRS,9aRS,9bRS)-3a,6,6,9a-tetramethyl-1,2,3a,4,6,7,8,9,9a,9b-decahydronaphtho[2,1-b]furanor (3aRS,9aRS,9bRS)-3a,6,6,9a-tetramethyl-1,2,3a,4,6,7,8,9,9a,9b-decahydronaphtho[2,1-b]furan,can be produced in an advantageous manner by means of a new andalternative method of cyclisation comprising an addition of an alcoholgroup on a carbon-carbon double bond.

Therefore, a first object of the present invention is a process for thepreparation of a furan of formula (I), or (I′)

-   -   in the form of a racemic or optically active diastereoisomer,        wherein the substituents in the positions 9a, 9b and 3a are in a        relative configuration cis, and the hydrogen atom in position 5a        and the oxygen atoms are in configuration trans relative to the        methyl in position 9a;        comprising the cyclisation of an alcohol of formula (II), or        respectively (II′)

-   -   wherein the dotted lines indicate the presence of one        carbon-carbon double bond in one of the indicated positions,        said compounds (II) or (II′) being in a racemic or optically        active form and, in the case of compound (II), being also in the        form of to diastereoisomer wherein the methyl in position 9a and        the hydrogen atom in position 5a are in the relative trans        configuration;        characterized in that said cyclisation is promoted by at least        one Lewis acid and optionally an additive.

For the sake of clarity, it is understood that by the expression “in aracemic or optically active form” it is intended that thediastereoisomer (I), (I′) or (II), or compound (II′) respectively, hasan enantiomeric excess (e.e.) ranging from 0 to 100%. For example aspecific compound (I) can be in the form of any mixture of the twoenantiomers of formulae (A) or (B)

wherein the indicated stereochemistry is absolute.

As well known by a person skilled in the art, it is understood that whenthe invention's process is used to obtain a compound (I) or (I′) in anoptically active form, then the corresponding compounds (II) or (II′)used as starting material or intermediates need to have an adequateoptical activity.

As typical examples of compounds (I) one may cite the following:

-   (3aR,9aR,9bR)-3a,6,6,9a-tetramethyl-1,2,3a,4,6,7,8,9,9a,9b-decahydronaphtho[2,1-b]furan,-   (3aRS,9aRS,9bRS)-3a,6,6,9a-tetramethyl-1,2,3a,4,6,7,8,9,9a,9b-decahydronaphtho[2,1-b]furan,-   (3aS,9aS,9bS)-3a,6,6,9a-tetramethyl-1,2,3a,4,6,7,8,9,9a,9b-decahydronaphtho[2,1-b]furan,-   (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan,-   (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan    or-   (3aS,5aR,9aR,9bS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan.

According to a particular embodiment of the invention, the invention'sprocess is particularly useful for the preparation of compound (I′) fromthe related compounds (II′), (III′), (IV′) and (V′).

According to a particular embodiment of the invention, the processes iscarried out using a compound (II) or (II′) of formula

wherein the stereochemistry is defined as for compounds (II) or (II′).

Compound (II) is a known compound, for instance see G. Frater andco-workers in WO 06/10287.

Compound (III) or (III′) can be prepared from the known compounds (IV)or (IV′) respectively

wherein the stereochemistry is defined as for compounds (II) or (II′);and which are reported by C. Fehr et al., in Org. Lett., 2006, 8, 1839,or by Danieswski et al. in J. Org. Chem., 1985, 50, 3963. Theenantiomerically pure compound (IV) or (IV′) can be obtained accordingto the method reported in Org. Lett., 2006, 8, 1839, and using anoptically active precursor (disclosed in WO 07/010,420).

The compounds of formula (III′) can thus be obtained by rearranging thepropargylic alcohol (IV) or (IV′) into the corresponding unsaturedaldehyde (V) or (V′)

wherein the stereochemistry is defined as for compounds (II) or (II′);and reduction of the aldehyde yields the alcohols (III) or (III′). Thepropargylic rearrangement can be performed, for instance, using theconditions reported in Tet. Lett., 1996, 37, 853 or in Tet. Lett., 1976,2981.

The reduction of the aldehyde into the alcohol can be performed, forinstance, using a metal hydride such as NaBH₄ or LiAlH₄.

This approach is further illustrated in the examples.

The compounds of formula (II′) or (III′) are new compounds and aretherefore, as valuable intermediates of the invention's process, anotherobject of the present invention. Specific examples of said novelcompounds are2-(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)ethanol.

As mentioned above, the invention's cyclisation is carried out byreacting compound (II) or (II′) with at least one Lewis acid andoptionally an additive.

Said Lewis acid can be used in stoechiometric or in catalytic amounts,relative to the starting alcohol.

Useful Lewis acids can be acidic clays, BF₃ derivatives or metal saltsof formula, AlCl₂R, MX₃ or ZnX₂, wherein R is a C₁-C₄ alkyl group, M isa trivalent metal cation selected from the group consisting of Al, Y, Scand Fe, and X represents a Cl or F atom or is a weakly ornon-coordinating mono anion.

Said acids can be in an anhydrous form or for some of them also in ahydrate form. Furthermore, the boron or aluminum derivative, especiallyBF₃, could be in the form of any one of its adducts with an ether orcarboxylic acid, such as R¹ ₂O or R²COOH, wherein R¹ is a C₁-C₅ alkylgroup, such as C₂H₅ or C₄H₉, and R² is a C₁-C₂₀ alkyl group, such amethyl, ethyl or hept-3-yl.

Non-limiting examples of acidic clays are, for instance, clays of theF-20X type.

Non-limiting examples of suitable weakly or non-coordinating mono anionsare ClO₄ ⁻, C₁₋₈ sulfonates, BF₄ ⁻, PF₆ ⁻, SbCl₆ ⁻, AsCl₆ ⁻, SbF₆ ⁻,AsF₆ ⁻ or BR⁴ ₄ ⁻, wherein R⁴ is a phenyl group optionally substitutedby one to five groups such as halide atoms or methyl or CF₃ groups.According to a particular embodiment of the invention, X is BF₄ ⁻, PF₆⁻, C₆F₅SO₃ ⁻, CF₃SO₃ ⁻, MeSO₃ ⁻, MeC₆H₄SO₃ ⁻ or Cl⁻.

According to a further particular embodiment of the invention, preferredLewis acids are BF₃ or a BF₃ adduct with a C₁-C₄ ether or carboxylicacid (such as Et₂O, Bu₂O or AcOH), FeX₃ or ScX₃, X being as definedabove.

As specific examples, but not limiting, of Lewis acids one may citeacids such as FeCl₃, Sc(CF₃SO₃)₃, or BF₃ ⁻(Et₂O)₂. Additives can beused, e.g. to increase the selectivity and/or the yield of thecyclisation.

As additive can be used a C₀-C₈ sulphonic acid, water, a C₁-C₁₂ alcohol,silica, aluminium oxide or molecular sieves. According to a particularembodiment said additive can be acidic or neutral, and in the form ofsmall particles, or even a powder.

Typical examples are butanol, neutral alumina, silica gel (e.g. of thetype commonly used for chromatography), or molecular sieves 4 Å. Typicalexamples of sulphonic acids are FSO₃H, MeSO₃H, MeC₆H₄SO₃H and thesimilar.

According to a particular embodiment, for the cyclisation a combinationof FeCl₃ and silica can be used. Alternatively a combination of FeCl₃and C₀-C₈ sulphonic acid or a combination of FeCl₃ and butanol can beused.

The Lewis acid can be added to the reaction medium in a large range ofconcentrations. As non-limiting examples, one can cite catalystconcentrations ranging from 0.01 to 1.50 molar equivalents, relative tothe molar amount of the starting alcohol (II) or (II′). Preferably, theLewis acid concentration will be comprised between 0.1 and 0.6 molarequivalents. It goes without saying that the optimum concentration ofacid will depend on the nature of the latter and on the desired reactiontime.

The additive can be added to the reaction medium in a large range ofconcentrations. As non-limiting examples, one can cite additiveconcentrations ranging from 10 to 250%, relative to the weight of theLewis acid. Preferably, the additive concentration will be comprisedbetween 10 and 120%, relative to the weight of the Lewis acid.

The cyclisation of the present invention in any of its embodiments canbe carried out in the presence or in the absence of solvent, but in anycase it is advantageously performed under anhydrous conditions.

However, according to a preferred embodiment of the invention, theprocess is advantageously carried out in the presence of a solvent. Asuitable solvent is one which is aprotic. Non-limiting examples of sucha solvent are ethers, esters, amides, aromatic hydrocarbons, linear orbranched or cyclic hydrocarbons, chlorinated solvents (in particularchlorinated hydrocarbon) and mixtures thereof. More preferably, thesolvent is a methylene chloride, 1,2-dichloroethane,1,2-dichlorobenzene, toluene and mixtures thereof. According to anotherembodiment of the invention, the reaction is carried out in a solvent ormixture of solvents having a dielectric constant below 25, at standardconditions (as indicated in the Handbook of Chemistry and Physics,87^(th) edition, 2006-2007).

The temperature, at which this process of the invention can be carriedout, in any of its embodiments, is comprised between −50° C. and 140°C., preferably between −10° C. and 80° C. Of course a person skilled inthe art is also able to select the preferred temperature as a functionof the melting and boiling point of the starting and final productsand/or an eventual solvent.

EXAMPLES

The invention, in all its embodiments, will now be described in furtherdetail by way of the following examples, wherein the abbreviations havethe usual meaning in the art, the temperatures are indicated in degreescentigrade (° C.); the NMR spectral data were recorded in CDCl₃ with a360 MHz or 100 MHz machine for ¹H or ¹³C respectively, the chemicaldisplacements δ are indicated in ppm with respect to TMS as standard,the coupling constants J are expressed in Hz.

Example 1 A) Preparation of2-(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)ethanol(1) Step A)

A solution of1-ethynyl-2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a-octahydro-1-naphthalenol(4.00 g; 17.2 mmol) in o-xylene (60 ml) was treated with[V₂O₆SiPh₂]_(n), (400 mg) [Tetrahedron Lett. 1976, 17, 2981] and heatedat reflux (145° C.). After 17 hours, the rearrangement was completed.The reaction mixture was poured into 5% aqueous NaOH. The product wasextracted twice with Et₂O and washed successively with H₂O and twicewith satured aqueous NaCl, dried (Na₂SO₄) and evaporated. Bulb-to-bulbdistillation (125° C. (oven temp.)/0.04 mbar) afforded 97% pure(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)acetaldehyde(3.42 g; yield=83%).

¹H-NMR: 1.13 (s, 3H), 1.14 (s, 3H), 1.77 (s, 3H), 1.10-1.35 (m, 2H),1.42-1.60 (m, 2H), 1.65 (s, 3H), 1.70-1.85 (m, 2H), 2.62-2.72 (m, 2H),3.11 (d, J=17 Hz, 1H), 3.22 (d, J=17 Hz, 1H), 5.66 (m, 1H), 9.55 (t, J=2Hz, 1H).

¹³C-NMR: 201.4 (d), 148.3 (s), 129.6 (s), 129.4 (s), 117.1 (d), 43.3(t), 40.6 (t), 39.2 (s), 37.5 (t); 36.1 (s), 33.6 (t), 32.8 (q), 30.5(q); 25.8 (q), 19.6 (q), 18.7 (t).

Step B)

A solution of(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)acetaldehydeobtained in step A) (3.40 g; 14.2 mmol) in Et₂O (10 ml) was addeddrop-wise to a stirred suspension of LiAlH₄ (410 mg; 10.7 mmol) in Et₂O(20 ml) at such a rate that a gentle reflux was maintained (5 minutes).The suspension was heated at reflux for 30 minutes, cooled at 0° C. andtreated successively drop-wise with water (0.4 ml), 5% aqueous NaOH (0.4ml) and water (3×0.4 ml). After stirring for 5 minutes at roomtemperature the suspension was filtered over Celite and the filtrateconcentrated. Bulb-to-bulb distillation (130° C. (oven temp.)/0.03 mbar)afforded pure2-(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)ethanol(1) (3.21 g; yield=90%).

¹H-NMR: 1.12 (s, 3H), 1.14 (s, 3H), 1.16 (s, 3H), 1.22-1.38 (m, 2H),1.45 (m, 1H), 1.55 (m, 1H), 1.70 (s, 3H), 1.72-1.85 (m, 2H), 1.91 (m,1H), 2.30 (m, 1H), 2.51 (m, 1H), 2.52-2.65 (m, 2H), 3.63 (m, 2H), 5.63(m, 1H).

¹³C-NMR: 149.0 (s), 133.8 (s), 127.0 (s), 117.1 (d), 62.6 (t), 40.7 (t),39.5 (s), 37.0 (t), 36.0 (s); 33.5 (t), 32.8 (q), 31.6 (t), 30.9 (q);26.0 (q), 19.6 (q), 18.8 (t).

B) Preparation of2-(2,5,5,8aβ-tetramethyl-3,4,4aα,5,6,7,8,8a-octahydro-1-naphthalenyl)ethanol(2) Step A)

A solution of 1-ethynyl-2,5,5,8a-tetramethyl-perhydro-4aH-1-naphthalenol(8.48 g; 92% pure; 33.3 mmol) in o-xylene (40 ml) was added drop-wise in20 minutes to a refluxing mixture (145° C.) of [Ph₃SiO]₃VO (1.79 g; 2.00mmol), triphenylsilanol (1.38 g; 5.00 mmol) and stearic acid (191 mg;0.67 mmol) in o-xylene (40 ml). After 7 hours the reaction mixture waspoured into 5% aqueous NaOH. The product was extracted twice with Et₂Oand washed successively with H₂O and twice with saturated aqueous NaCl,dried (Na₂SO₄) and evaporated. Bulb-to-bulb distillation (125° C. (oventemp.)/0.03 mbar) afforded 87% pure(2,5,5,8aβ-tetramethyl-3,4,4aα,5,6,7,8,8a-octahydro-1-naphthalenyl)acetaldehyde(7.59 g; yield=85%).

Using [V₂O₆SiPh₂]_(n) also afforded(2,5,5,8aβ-tetramethyl-3,4,4aα,5,6,7,8,8a-octahydro-1-naphthalenyl)acetaldehydein 85% yield.

¹³C-NMR: 201.5 (d), 132.1 (s), 131.3 (s), 51.7 (d), 43.2 (t), 41.5 (t),38.5 (s), 37.2 (t), 33.9 (t); 33.3 (s), 33.2 (q), 21.6 (q), 19.9 (q);19.8 (q), 18.9 (t), 18.9 (t).

Step B)

A solution of(2,5,5,8aβ-tetramethyl-3,4,4aα,5,6,7,8,8a-octahydro-1-naphthalenyl)acetaldehyde(7.58 g; 87% pure; 28.2 mmol) in Et₂O (50 ml) was added drop-wise to astirred suspension of LiAlH₄ (800 mg; 21.1 mmol) in Et₂O (20 ml) at sucha rate that a gentle reflux was maintained (5 minutes). The suspensionwas heated at reflux for 30 minutes, cooled at 0° C. and treatedsuccessively drop-wise with water (0.8 ml), 5% aqueous NaOH (0.8 ml) andwater (3×0.8 ml). After stirring for 5 minutes at room temperature, thewhite suspension was filtered over Celite and the filtrate concentrated.Bulb-to-bulb distillation (130° C. (oven temp.)/0.03 mbar) afforded 94%pure2-(2,5,5,8aβ-tetramethyl-3,4,4aα,5,6,7,8,8a-octahydro-1-naphthalenyl)ethanol(2) (6.98 g; 94% pure; yield=99%).

¹³C-NMR: 136.2 (s), 128.6 (s), 62.7 (t), 51.7 (d), 41.7 (t), 38.7 (s),37.2 (t), 33.7 (t), 33.3 (s); 33.3 (q), 31.5 (t), 21.7 (q), 20.1 (q);19.9 (q), 19.0 (t), 19.0 (t).

Example 2 A) Cyclisation of2-(2,5,5,8aβ-tetramethyl-3,4,4aα,5,6,7,8,8a-octahydro-1-naphthalenyl)ethanol(2)

Using FeCl₃ and SiO₂:

A solution of2-(2,5,5,8aβ-tetramethyl-3,4,4aα,5,6,7,8,8a-octahydro-1-naphthalenyl)ethanol(2) (500 mg; 94% pure; 1.99 mmol) in 1,2-dichloroethane (5 ml) andCH₂Cl₂ (8 ml) was treated at 24° C. with SiO₂ 60 Å (70-220 μm) (81 mg).Under stirring anhydrous FeCl₃ (162 mg; 1.00 mmol) was added. After 20minutes the dark reaction mixture was poured under stirring into 5%aqueous HCl and was extracted twice with Et₂O. The organic phase waswashed successively with water, sutured aqueous NaHCO₃ and twice withsaturated aqueous NaCl e, dried (Na₂SO₄) and evaporated (513 mg).Bulb-to-bulb distillation (125° C. (oven temp.)/0.06 mbar) afforded (3)(481 mg; 77% pure; yield=79%), containing recovered (2) (yield=13%).

B) Cyclisation of2-(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)ethanol(1)

Using FeCl₃ and SiO₂:

A solution of2-(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)ethanol(1) (500 mg; 96% pure; 2.05 mmol) in 1,2-dichloroethane (5 ml) andCH₂Cl₂ (8 ml) was treated at 24° C. with SiO₂ 60 Å (70-220 μm) (84 mg).Under stirring FeCl₃ (glove-box stored; 167 mg; 1.03 mmol) was added.After 20 min the dark reaction mixture was poured under stirring into 5%HCl and was extracted with Et₂O (2×). The organic phase was washedsuccessively with water, sat. aq. NaHCO₃ and saturated aqueous NaCl,dried (Na₂SO₄) and evaporated. Bulb-to-bulb distillation (125° C. (oventemp.)/0.06 mbar) afforded (±)-(5) (454 mg; 81% pure; yield=73%). It wasalso obtained (6) (yield=4%) and (7) (yield=2%).

It was also recovered (1) (yield=8%).

Using FeCl₃ in Stoichiometric Amounts:

A solution of2-(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)ethanol(300 mg; 1.28 mmol) in CH₂Cl₂ (4 ml) and 1,2-dichloroethane (2 ml) wastreated at 0° C. with FeCl₃ (208 mg; 1.28 mmol). After 40 minutes theconversion was completed. The reaction mixture was poured under stirringinto 5% aqueous HCl and was extracted twice with Et₂O. The organic phasewas washed successively with water, saturated aqueous NaHCO₃ and twicewith saturated aqueous NaCl, dried (Na₂SO₄) and evaporated. Bulb-to-bulbdistillation (115° C. (oven temp.)/0.03 mbar) afforded pure (±)-(5) (198mg; 96% pure; yield=63%) containing traces of (6) (yield=2%).

Using FeCl₃ in Catalytic Amounts:

A solution of(+)-2-(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)ethanol*([α]_(D) ²⁰+45 (CHCl₃; c: 0.84; 1.0 g; 4.27 mmol) in 1,2-dichloroethane(20 ml) was treated at 0° C. with anhydrous FeCl₃ (138 mg; 0.848 mmol).After 2 minutes, the temperature was allowed to reach room temperature.Stirring was to continued for 3 hours, then another portion of anhydrousFeCl₃; (69 mg; 0.424 mmol) was added and stirring continued for 30minutes. The reaction mixture was stopped at partial conversion bypouring it under stiffing into 5% aqueous HCl and was extracted twicewith Et₂O. The organic phase was washed successively with water,saturated aqueous NaHCO₃ and twice with saturated aqueous NaCl, dried(Na₂SO₄) and evaporated. Purification by column chromatography (SiO₂ (60g); cyclohexane/AcOEt=99:1), afforded 159 mg of first fractions(containing appreciatively 39% of (+)-(5), 27% of (6) and 9% of(+)-(7)), followed by 423 mg (yield=42%) of pure (+)-(5) (93% ee;[α]_(D) ²⁰+84 (CHCl₃; c: 0.92; 739 mg) and then usingcyclohexane/AcOEt=9:1, 316 mg (yield=32%) of (+)-(1) were recovered.

*prepared from (−)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)butanalprepared according the procedure described in WO 2007/010420

Example 3

Following the same experimental procedure as described in Example 2,other Lewis acids have been tested.

The results for the cyclisation of (2) are reported in the followingTable I:

N° Lewis acid ¹⁾ Additive ²⁾ Solvent ³⁾ T (° C.) t ⁴⁾ Res. ⁵⁾ (2) ⁶⁾ (3)⁶⁾ (4) ⁶⁾ (3)/(4) ⁷⁾ 1 SC(OTf)₃ — CH₂Cl₂ 20 6 h. 60 30 0 >100    (0.2) 2FeCl₃ — (ClCH₂)₂ 20 3 h 32 57 1 57 (0.25) 3 FeCl₃ — (ClCH₂)₂ 10 3 h 2311 78 0 >100    (0.50) CH₂Cl₂ (½) 4 FeCl₃ SiO₂ (ClCH₂)₂ 20 20 min 6 1177 1 77 (0.50) (50%) CH₂Cl₂ (½) 5 FeCl₃ SiO₂ toluene 20 2 h. 6 13 74 237 (0.50) (50%)  6* MeSO₃H — CH₂Cl₂   0° 20 min 12 2 81 5 16 (1.28) p.s.it was used the starting material obtained in Example 1 (94% purity) ¹⁾between brackets is the molar amount relative to starting alcohol (2) ²⁾between brackets is the w/w amount relative to Lewis acid ³⁾ the w/wratio between (2) and the solvent is the same as in Example 2), betweenbrackets it is the w/w ratio between two solvents ⁴⁾ reaction time ⁵⁾non-volatile products recovered other than (2), (3) and (4), w/wpercentage relative to the amount of (2) initially used (%) ⁶⁾ relativeamounts obtained by GC analysis of the volatile fraction (%) ⁷⁾ molarratio OTf = triflate-*: comparative example (prior art conditions-WO06/10287)

It is evident from said Table I that the invention's process is able todeliver yields as good as those obtainable by the use of the standardmethod (a strong protic acid only), and in addition the invention'sprocess allows to obtain the desired product with a much higherselectivity compared to the one allowed by the use of a strong proticacid only.

The results for the cyclisation of a mixture of isomers of formula (II)(ambrols) are reported in the following Table II:

N° Lewis acid ¹⁾ Additive ²⁾ Solvent ³⁾ T (° C.) t ⁴⁾ Res. ⁵⁾ SM ⁶⁾ (3)⁶⁾ (4) ⁶⁾ (3)/(4) ⁷⁾ 1 FeCl₃ SiO₂ (ClCH₂)₂ 20 40 min. 3 18 73 4 18(0.50) (50%) 2 FeCl₃ MeSO₃H (ClCH₂)₂ 20 10 min. 2  9 79 6 13 (0.2)(0.2)** CH₂Cl₂ (½) 3 MeSO₃H — CH₂Cl₂ 20 45 min. 8 23 67 6 11 (1.28) SM:starting alcohol ¹⁾ between brackets is the molar amount relative tostarting alcohol ²⁾ between brackets is the w/w amount relative to Lewisacid; **molar amount relative to starting alcohol ³⁾ the w/w ratiobetween SM and the solvent is the same as in Example 2), betweenbrackets it is the w/w ratio between two solvents ⁴⁾ reaction time ⁵⁾non-volatile products recovered other than starting alcohol, (3) and(4), w/w percentage relative to the amount of alcohol initially used (%)⁶⁾ relative amounts obtained by GC analysis of the volatile fraction (%)⁷⁾ molar ratio OTf = triflate-*: comparative example (prior artconditions-WO 06/10287)

It is evident from said Table II that, by using a mixture of ambrols,the invention's process is able to deliver yields higher than thoseobtainable by the use of the standard method (a strong protic acidonly), and with significantly higher selectivities than the one obtainedby the use of a strong protic acid only.

The results for the cyclisation of a mixture of isomers of formula (II)(ambrols) are reported in the following Table III:

Lewis Addi- Sol- T (3)/ N° acid ¹⁾ tive ²⁾ vent ³⁾ (° C.) t ⁴⁾ SM ⁵⁾ (3)⁵⁾ (4) ⁵⁾ (4) ⁶⁾ 1 FeCl₃ SiO₂ MeNO₂ 20 30 30 46 7 6.5 (0.50) (50%) min.   2 ⁸⁾ TsOH ⁷⁾ — MeNO₂ 20 60 60 33 3.5 9.5 (2.0) min. 3 TsOH — MeNO₂ 2024 15 57 24 2.4 (2.0) h. SM: starting alcohol ¹⁾ between brackets is themolar amount relative to starting alcohol ²⁾ between brackets is the w/wamount relative to Lewis acid; ** molar amount relative to startingalcohol ³⁾ the w/w ratio between SM and the solvent is the same as inExample 2), between brackets it is the w/w ratio between two solvents ⁴⁾reaction time ⁵⁾ relative amounts obtained by GC analysis of thevolatile fraction (%) ⁶⁾ molar ratio ⁷⁾ TsOH is MeC₆H₄SO₃H ⁸⁾ reactionwas not finished.

It is evident from said Table III that the invention's process is muchfaster than the prior art process, since it is finished in only 30minutes, to give industrially interesting conversions. Furthermore, atthe end of the conversion, it is also evident that the invention'sprocess, although giving slightly lower amounts of the desired product,allows much higher selectivity than the one obtained by the use of astrong protic acid only.

The results for the cyclisation of (1) are reported in the followingTable IV:

N° Lewis acid ¹⁾ Additive ²⁾ Solvent ³⁾ T (° C.) t ⁴⁾ (1) ⁵⁾ (5) ⁵⁾(6) + (7) ⁵⁾ 1 FeCl₃ — (ClCH₂)₂ 20 3.5 h.  7 68 11 (0.25) 2 FeCl₃ SiO₂(ClCH₂)₂ 20 20 min.  8 81  6 (0.50) (50%) CH₂Cl₂ (½) 3 Sc(OTf)₃ — CH₂Cl₂20 3 h. 21 56 12 (0.2) 4 BF₃(OEt)₂ — CH₂Cl₂ 20 4 h. 29 61  4 (1.1) p.s.it was used the starting material obtained in Example 1 (94% purity) ¹⁾between brackets is the molar amount relative to starting alcohol (2) ²⁾between brackets is the w/w amount relative to Lewis acid ³⁾ the w/wratio between (2) and the solvent is the same as in Example 2), betweenbrackets it is the w/w ratio between two solvents ⁴⁾ reaction time ⁵⁾relative amounts obtained by GC analysis of the volatile fraction (%)OTf = triflate

When the cyclisation of (1) with MeSO₃H (prior art conditions—WO06/10287) was attempted (1.3 molar equivalent, T 20° C.) a very complexmixture was obtained, wherein the desired furan (5) accounted for lessthan 5% of the total and many unknown products were obtained (accountingfor more than 30%).

The same cyclisation with ClSO₃H (1.0 molar equivalent, T −78° C.,MeNO₂) afforded only a rearrangement product(3a,5a,6,6-tetramethyl-1,2,3a,4,5,5a,6,7,8,9-perhydronaphtho[2,1-b]furan)in about 25% yield.

1.-8. (canceled)
 9. A process for the preparation of a furan of formula(I), or (I′)

in the form of a racemic or optically active diastereoisomer, whereinthe substituents in the positions 9a, 9b and 3a are in a relativeconfiguration cis, and the hydrogen atom in position 5a and the oxygenatoms are in configuration trans relative to the methyl in position 9a;which comprises cyclizing an alcohol of formula (II), or respectively(II′)

wherein the dotted lines indicate the presence of one carbon-carbondouble bond in one of the indicated positions, said compounds (II) or(II′) being in a racemic or optically active form and, in the case ofcompound (II), being also in the form of diastereoisomer wherein themethyl in position 9a and the hydrogen atom in position 5a are in therelative trans configuration; while promoting the cyclizing with atleast one Lewis acid and optionally an additive to assist in increasingselectivity or yield of the cyclizing.
 10. The process according toclaim 9, wherein the compounds (II) or (II′) are respectively of formula(III) or (III′)

wherein the stereochemistry is defined as for compounds (II) or (II′).11. The process according to claim 9, wherein the compound of formula(I) or (I′) is optically active.
 12. The process according to claim 9,wherein the compound of formula (I) or (I′) is:(3aR,9aR,9bR)-3a,6,6,9a-tetramethyl-1,2,3a,4,6,7,8,9,9a,9b-decahydronaphtho[2,1-b]furan,(3aRS,9aRS,9bRS)-3a,6,6,9a-tetramethyl-1,2,3a,4,6,7,8,9,9a,9b-decahydronaphtho[2,1-b]furan,(3aS,9aS,9bS)-3a,6,6,9a-tetramethyl-1,2,3a,4,6,7,8,9,9a,9b-decahydronaphtho[2,1-b]furan,(3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan,(3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan,or(3aS,5aR,9aR,9bS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan.13. The process according to claim 9, wherein the Lewis acid is selectedfrom the group consisting of acidic clays, BF₃ derivatives, metal saltsof formula AlCl₂R, MX₃ or ZnX₂, wherein R is a C₁-C₄ alkyl group, M is atrivalent metal cation selected from the group consisting of Al, Y, Scand Fe, and X represents a Cl or F atom or is a weakly ornon-coordinating mono anion.
 14. The process according to claim 13,wherein said BF₃ derivatives a BF₃ adducts with an ether or carboxylicacid, such as R¹ ₂O or R²COOH, wherein R¹ is a C₁-C₅ alkyl group, and R²is a C₁-C₂₀ alkyl group.
 15. The process according to claim 13, whereinsaid weakly or non-coordinating mono anion is selected from the groupconsisting of ClO₄ ⁻, C₁₋₈ sulfonates, BF₄ ⁻, PF₆ ⁻, SbCl₆ ⁻, AsCl₆ ⁻,SbF₆ ⁻, AsF₆ ⁻ or BR⁴ ₄ ⁻, wherein R⁴ is a phenyl group optionallysubstituted by one to five groups such as halide atoms or methyl or CF₃groups.
 16. The process according to claim 13, wherein X is BF₄ ⁻, PF₆⁻, C₆F₅SO₃ ⁻, CF₃SO₃ ⁻, MeSO₃ ⁻, MeC₆H₄SO₃ ⁻ or Cl⁻.
 17. The processaccording to claim 13, wherein the Lewis acid is FeCl₃, Sc(CF₃SO₃)₃, OrBF₃ ⁻(Et₂O)₂.
 18. The process according to claim 9, which is conductedby reacting compound (II) or (II′) with at least one Lewis acid and atleast one additive of a C₀-C₈ sulphonic acid, water, a C₁-C₁₂ alcohol,silica, aluminium oxide or molecular sieves.
 19. The process accordingto claim 18, wherein the Lewis acid is FeCl₃ and the additive is a C₀-C₈sulphonic acid, butanol or silica.
 20. A compound of formula

in the form of any one of its stereoisomers or mixtures thereof.